The central goal of this new Program Project is to understand the role of the hormone melatonin on the brain structures [especially the suprachiamatic nuclei (SCN) in the hypothalamus] that generate the sleep- alertness rhythm (as well as other circadian rhythms); and to understand the significance of aging on this system. This understanding will be accelerated by an alliance of basic and clinical scientists who will be working closely together on this goal. This program will accomplish the following aims: 1) Melatonin will be administered to elderly human subjects at different times of the day, in order to measure phase-shifts in the timing of the endogenous melatonin rhythm, and to thereby construct a phase response curve (PRC). this PRC will be compared to the PRC obtained in another project for younger subjects, and will be interpreted as a measure of the responsiveness of the circadian system in elderly people. 2) Melatonin administration will also be tested as a means of increasing the quality and quantity of sleep in elderly subjects. 3) Melatonin administration will be tested as a means of shifting the circadian phase in aging subjects whose rhythms are desynchronized because of shift work. 4) Molecular clones encoding functional melatonin receptors will be isolated and characterized which will elucidate the molecular and cellular actions of melatonin. 5) The electrical activity and response of individual cells within the SCN will be studied with the aim of understanding the fundamental mechanisms by which this structure generates a 24-hour rhythm and responds to melatonin. Because of the close collaboration fostered by this program, insights gained at the basic level can be quickly and efficiently tested in human subjects. In turn, the behavioral and physiological knowledge gained from human studies can guide the search for basic mechanisms. The knowledge gained by this research program will provide the basis for the rational assessment and intervention of circadian abnormalities of the sleep/wake cycle in elderly patients, thus promoting consolidated, restorative sleep, at the preferred time of the night (or day).